National strategies for knowledge translation in health policy-making: A scoping review of grey literature.

BACKGROUND AND OBJECTIVES: Without strategic actions in its support, the translation of scientific research evidence into health policy is often absent or delayed. This review systematically maps and assesses national-level strategic documents in the field of knowledge translation (KT) for health policy, and develops a practical template that can support Evidence-informed Policy Network (EVIPNet) Europe countries in producing national strategies for evidence-informed policy-making. METHODS: Websites of organizations with strategic responsibilities in KT were electronically searched, on the basis of pre-defined criteria, in July-August 2017, and an updated search was carried out in April-June 2021. We included national strategies or elements of national strategies that dealt with KT activities, as well as similar strategies of individual institutions with a national policy focus. Two reviewers screened the strategies for inclusion. Data were analysed using qualitative content analysis. RESULTS: A total of 65 unique documents were identified, of which 17 were eligible and analysed for their structure and content. Of the 17, 1 document was a national health KT action plan and 6 documents were institution-level KT strategies. The remaining 10 strategies, which were also included were 2 national health strategies, 5 national health research strategies and 3 national KT strategies (not specific to the field of health alone). In all, 13 structural elements and 7 major themes of health policy KT strategies were identified from the included documents. CONCLUSION: KT in health policy, as emerged from the national strategies that our mapping identified, is based on the production and accessibility of policy-relevant research, its packaging for policy-making and the activities related to knowledge exchange. KT strategies may play different roles in the complex and context-specific process of policy-making. Our findings show that the main ideas of health-specific evidence-informed policy literature appear in these strategies, but their effectiveness depends on the way stakeholders use them. Specific knowledge-brokering institutions and organizational capacity, advocacy about the use of evidence, and close collaboration and co-decision-making with key stakeholders are essential in furthering the policy uptake of research results.

Current and emerging biomarkers in ovarian cancer diagnosis; CA125 and beyond.

Ovarian cancer (OC) is one of the most common causes of cancer-related death in women worldwide. Its five-year survival rates are worse than the two most common gynecological cancers, cervical and endometrial. This is because it is asymptomatic in the early stages and usually detected in the advanced metastasized stage. Thus, survival is increasingly dependent on timely diagnosis. The delay in detection is contributed partly by the occurrence of non-specific clinical symptoms in the early stages and the lack of effective biomarkers and detection approaches. This underlines the need for biomarker identification and clinical validation, enabling earlier diagnosis, effective prognosis, and response to therapy. Apart from the traditional diagnostic biomarkers for OC, several new biomarkers have been delineated using advanced high-throughput molecular approaches in recent years. They are currently being clinically evaluated for their true diagnostic potential. In this chapter, we document the commonly utilized traditional screening markers and recently identified emerging biomarkers in OC diagnosis, focusing on secretory and protein biomarkers. We also briefly reviewed the recent advances and prospects in OC diagnosis.

Cross-talk between the microbiome and chronic inflammation in esophageal cancer: potential driver of oncogenesis.

Esophageal cancer (EC) is frequently considered a lethal malignancy and is often identified at a later stage. It is one of the major causes of cancer-related deaths globally. The conventional treatment methods like chemotherapy, radiotherapy, and surgery offer limited efficacy and poor clinical outcome with a less than 25% 5-year survival rate. The poor prognosis of EC persists despite the growth in the development of diagnostic and therapeutic modalities to treat EC. This underlines the need to elucidate the complex molecular mechanisms that drive esophageal oncogenesis. Apart from the role of the tumor microenvironment and its structural and cellular components in tumorigenesis, mounting evidence points towards the involvement of the esophageal microbiome, inflammation, and their cross-talk in promoting esophageal cancer. The current review summarizes recent research that delineates the underlying molecular mechanisms by which the microbiota and inflammation promote the pathophysiology of esophageal cancer, thus unraveling targets for potential therapeutic intervention.

What do we know about evidence-informed priority setting processes to set population-level health-research agendas: an overview of reviews.

BACKGROUND: This overview aimed to synthesize existing systematic reviews to produce a draft framework of evidence-informed health priority setting that supports countries in identifying appropriate steps and methods when developing and implementing national research agendas. MAIN BODY: We searched Ovid MEDLINE® and the WHO Institutional Repository for Information Sharing from 2010 to 2020 for critical or systematic reviews that evaluated research priority setting exercises. We adapted the AMSTAR checklist to assess the quality of included reviews and used adapted frameworks for data extraction and analysis. The search resulted in 2395 titles, of which 31 were included. Populations included in the reviews typically involved patients, families and carers, researchers, clinicians, policymakers and research funders. The topics covered in the reviews varied from specific diseases or conditions, approaches for healthcare practice or research priority setting methods itself. All the included systematic reviews were of low or critically low quality. The studies were thematically grouped based on their main focus: identifying and engaging with stakeholders; methods; context; and health area. CONCLUSION: Our overview of reviews has reconfirmed aspects of existing frameworks, but has also identified new concepts for countries to consider while developing their national research agendas. We propose a preliminary framework for consideration that highlights four key phases: (1) preparatory, (2) priority setting, (3) follow-up phase and (4) sustainability phase, which have thirteen sub-domains to consider.

Translating health information into policy-making: A pragmatic framework.

Knowledge translation (KT) is increasingly acknowledged to have the potential to improve policy-making. The value of health information (HI), as part of the KT context, is now also increasingly understood. This paper aims to identify existing tools for the translation of HI into policy-making and to develop a related framework facilitating future application of these identified tools. Updating and building upon a scoping review undertaken for the Health Evidence Network (HEN) Synthesis Report No. 54, commissioned by the World Health Organization (WHO) Regional Office for Europe in 2017, a literature search was conducted using the same databases (PubMed and Scopus) and the same keywords as in the WHO/HEN scoping review. All papers elaborating on tools enhancing the use of HI in policy-making were included. Of the 2549 records screened, 17 publications were included in this study. This review identified four different types of tools: 1) Visualisation and modelling tools, 2) Information packaging and synthesis tools, 3) Communication and dissemination tools and 4) Information linkage and exchange tools. The distinctions between these are fluid as different tools can be combined or incorporated into one another to complement each other. Our framework shows that communication/dissemination or linkage tools are crucial to effectively inform policy decisions through HI. This study helps to understand and guide the processes of KT of HI.

Assessing the impact of knowledge communication and dissemination strategies targeted at health policy-makers and managers: an overview of systematic reviews.

BACKGROUND: The use of research evidence as an input for health decision-making is a need for most health systems. There are a number of approaches for promoting evidence use at different levels of the health system, but knowledge of their effectiveness is still scarce. The objective of this overview was to evaluate the effectiveness of knowledge communication and dissemination interventions, strategies or approaches targeting policy-makers and health managers. METHODS: This overview of systematic reviews used systematic review methods and was conducted according to a predefined and published protocol. A comprehensive electronic search of 13 databases and a manual search in four websites were conducted. Both published and unpublished reviews in English, Spanish or Portuguese were included. A narrative synthesis was undertaken, and effectiveness statements were developed, informed by the evidence identified. RESULTS: We included 27 systematic reviews. Three studies included only a communication strategy, while eight only included dissemination strategies, and the remaining 16 included both. None of the selected reviews provided "sufficient evidence" for any of the strategies, while four provided some evidence for three communication and four dissemination strategies. Regarding communication strategies, the use of tailored and targeted messages seemed to successfully lead to changes in the decision-making practices of the target audience. Regarding dissemination strategies, interventions that aimed at improving only the reach of evidence did not have an impact on its use in decisions, while interventions aimed at enhancing users' ability to use and apply evidence had a positive effect on decision-making processes. Multifaceted dissemination strategies also demonstrated the potential for changing knowledge about evidence but not its implementation in decision-making. CONCLUSIONS: There is limited evidence regarding the effectiveness of interventions targeting health managers and policy-makers, as well as the mechanisms required for achieving impact. More studies are needed that are informed by theoretical frameworks or specific tools and using robust methods, standardized outcome measures and clear descriptions of the interventions. We found that passive communication increased access to evidence but had no effect on uptake. Some evidence indicated that the use of targeted messages, knowledge-brokering and user training was effective in promoting evidence use by managers and policy-makers.

Assessing the impact of knowledge communication and dissemination strategies targeted at health policy-makers and managers: an overview of systematic reviews

The use of research evidence as an input for health decision-making is a need for most health systems. There are a number of approaches for promoting evidence use at different levels of the health system, but knowledge of their effectiveness is still scarce. The objective of this overview was to evaluate the effectiveness of knowledge communication and dissemination interventions, strategies or approaches targeting policy-makers and health managers.

Extensive selective reporting of quality of life in clinical study reports and publications of placebo-controlled trials of antidepressants.

BACKGROUND: Selective reporting of trial results is common. OBJECTIVE: To study selective reporting in clinical study reports, company trial registers and publications of quality of life in placebo-controlled trials of antidepressants. METHODS: We compared clinical study reports of four antidepressants (fluoxetine, duloxetine, paroxetine and sertraline) obtained from two European drug regulators, data from online company registers, and publications received or retrieved from Eli Lilly and GlaxoSmithKline. Pfizer was also contacted but did not provide any publications. RESULTS: We included 15 trials (19,015 pages) and 4717 patients. Six trials had used SF-36, seven EQ-5D and two both instruments. Nine of the 15 CSRs (60%) displayed selective reporting. In the companies' online registers, there was selective reporting for all 15 trials (100%). We received 20 publications from Eli Lilly and retrieved six from the GlaxoSmithKline register. There was selective reporting in 24 of the 26 publications (92%). Despite extensive selective reporting, we found only small differences between placebo and active drugs. CONCLUSIONS: Access to the full raw data from clinical trials and to case report forms for all patients are needed to evaluate the effect of antidepressants on quality of life. Regulatory agencies should refuse to approve drugs or new indications based on incomplete reporting.

Cost-effectiveness and resource allocation (CERA) 18 years of evolution: maturity of adulthood and promise beyond tomorrow.

Since its inception in 2003, Cost Effectiveness and Resource Allocation journal has come a long way over the past 18 years. Possibly much longer than many of its contemporaries in the blossoming science of health economics might have anticipated. Today, entering 2020 it celebrates the Age of Maturity. We believe that in the third decade of XXI century the interdisciplinary science of health economics, will rejuvenate and come back to us younger than ever from its early historical roots almost a century ago. The spreading of economic globalization in several distinctive ways, either led by multinational business corporations or newly emerged Asian leadership, or both, is likely to make challenges for contemporary health systems far more serious. The fourth industrial revolution (cyber physical systems and artificial intelligence technology) and accelerated innovation in the field of E-Health and digital health, will probably change the workflow in medical and health care, and inevitably transform the labour market in the upcoming decades. So, let us be up to the task. Let us provide academic centres, industry-sponsored pharmaceutical and medical device innovation hubs, and governing authorities alike, with a powerful forum for debate on cost-effective resource allocation in the years to come.

Drop-out rates in placebo-controlled trials of antidepressant drugs: A systematic review and meta-analysis based on clinical study reports.

OBJECTIVE: To study the drop-out rates in trials of selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs). METHODS: This study is a systematic review and meta-analysis of trials. The main outcome measure: Overall drop-out rate. Secondary outcomes were drop-outs due to adverse events and lack of effect. We obtained clinical study reports (CSRs) of five antidepressant drugs from the European Medicines Agency and the UK's Medicines and Healthcare products Regulatory Agency. The eligibility criteria for selecting studies: double-blind randomised, placebo-controlled trials for any indication. DATA EXTRACTION AND ANALYSIS: The primary outcome was extracted by two researchers independently and meta-analysed using the Mantel-Haenszel method (fixed effect model). The secondary outcomes were extracted by one researcher and checked by another. Sensitivity analyses were performed using Peto's odds ratio and beta binomial methods, due to presence of null events, and by excluding unreliable trials. RESULTS: We included 71 CSRs (67,319 pages) with information on 73 trials (11,057 patients on SSRI or SNRI drugs, and 7,369 on placebo). There were minor discrepancies within the CSRs when a modified intention to treat principle was used and patients lost to follow up early in the trial were not accounted for. Significantly more patients dropped out on active drug than on placebo, risk ratio 1.08 (95% CI 1.03 to 1.13), with no difference between adults and children/ adolescents, RR = 1.08 (1.03 to 1.13) and 1.07 (0.95 to 1.21), respectively. When three trials with a prior single-blind phase on active drug were removed, the difference was a risk ratio of 1.12 (1.07 to 1.18), whereas the result was the same after removal of three trials with fraudulent data or other issues with data validity, risk ratio 1.08 (1.03 to 1.13). There were more drop-outs due to adverse events on active drug than on placebo, risk ratio 2.63 (2.33 to 2.96). There were fewer drop-outs due to lack of effect, risk ratio 0.47 (0.43 to 0.53). However, this result is biased; when more people drop out due to adverse effects, fewer can drop out because of lack of effect. CONCLUSIONS: By using CSRs, we were able to demonstrate for the first time that more patients dropped out on active drug than on placebo. As it can be argued that the drop-out rate reflects the patients' overall assessment of the balance between benefits and harms, our review adds to the growing concern that SSRIs and SNRIs might not have the desired effect. Our review also highlights the importance of using CSRs for undertaking reviews of drugs.

Empirical evidence of delays in diagnosis and treatment of pulmonary tuberculosis: systematic review and meta-regression analysis.

BACKGROUND: Delays in diagnosis and treatment of pulmonary tuberculosis are a major set-back to global tuberculosis control. There is currently no global evidence on the average delays thus, the most important contributor to total delay is unknown. We aimed to estimate average delay measures and to investigate sources for heterogeneity among studies assessing delay measures. METHODS: Systematic review of studies reporting mean (± standard deviation) or median (interquartile range, IQR) of patient, doctor, diagnostic, treatment, health system and/or total delays in journal articles indexed in PubMed. We pooled mean delays using random-effects inverse variance meta-analysis, investigated for variations in pooled estimates in subgroup analyses and explored for sources of heterogeneity using pre-specified explanatory variables. RESULTS: The systematic review included 198 studies (831,724 patients) from 78 countries. The median number of patients per study was 243 (IQR; 160-458) patients. Overall, the pooled mean total delay was 87.6 (95% CI: 81.4-93.9) days. The most important and largest contributor to total delay was patient delay with a pooled mean delay of 81 (95% CI: 70-92) days followed by doctor's delay and treatment delay with pooled mean delays of 29.5 (95% CI: 25.9-33.0) and 7.9 (95% CI: 6.9-8.9) days respectively. There was considerable heterogeneity in all pooled analyses (I2 > 95%). In the meta-regression models of mean delays, studies excluding extra-pulmonary tuberculosis patients reported increased mean doctor's delay by 45 days on average, non-use of chest x-ray and conducting studies in high income countries decreased mean treatment delay by 20 and 22 days on average, respectively. CONCLUSION: Strategies to address patients' delay could have important implications for the success of the global tuberculosis control programmes.

Serodiagnostic evaluation of recombinant CdtB of S. Typhi as a potential candidate for acute typhoid.

Typhoid fever caused by human restricted Salmonella typhi presents a considerable health burden on developing South-Asian nations like India. The suboptimal sensitivity and specificity associated with culture-based isolation of etiological agent and the extensively used surface antigen-based serological assays often lead to misdiagnosis and inappropriate antimicrobial treatment. The increasing reports of the emergence of resistant strains and undefined disease burden signify the critical need for an inexpensive, reliable, easy-to-use, and highly sensitive diagnostic test for typhoid fever. Utilizing S. typhi-specific and immunogenic antigens in sero-diagnostic assays could lead to precise diagnosis of acute typhoid and prompt treatment. In this study, we report cloning, expression, and purification of recombinant Cytolethal distending toxin subunit B (CdtB) of S. typhi, which is reported to be highly specific, immunogenic, and expressed only upon S. typhi infection. We further evaluated the purified recombinant CdtB for its diagnostic potential in an IgM-based indirect ELISA format using 33 human samples. Twenty-one serum samples from blood culture confirmed cases (n = 21) of typhoid and 12 samples from healthy controls (n = 12) were tested. The assay showed sensitivity of 100% and specificity of 83.3% respectively with positive and negative predictive values of 91.3 and 100% respectively. Efficient detection of specific IgM antibodies indicates that CdtB could be highly valuable in sero-diagnosis of acute typhoid and rapid screening of clinical samples.

Using HTA and guideline development as a tool for research priority setting the NICE way: reducing research waste by identifying the right research to fund.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) was established in 1999 and provides national guidance and advice to improve health and social care. Several steps in the research cycle have been identified that can support the reduction of waste that occurs in biomedical research. The first step in the process is ensuring appropriate research priority setting occurs so only the questions that are needed to fill existing gaps in the evidence are funded. This paper summarises the research priority setting processes at NICE. METHODS: NICE uses its guidance production processes to identify and prioritise research questions through systematic reviews, economic analyses and stakeholder consultations and then highlights those priorities by engagement with the research community. NICE also highlights its methodological areas for research to ensure the appropriate development and growth of the evidence landscape. RESULTS: NICE has prioritised research questions through its guidance production and methodological work and has successfully had several research products funded through the National Institute for Health Research and Medical Research Council. This paper summarises those activities and results. CONCLUSIONS: This activity of NICE therefore reduces research waste by ensuring that the research it recommends has been systematically prioritised through evidence reviews and stakeholder input.

Benzodiazepines for psychosis-induced aggression or agitation.

BACKGROUND: Acute psychotic illness, especially when associated with agitated or violent behaviour, can require urgent pharmacological tranquillisation or sedation. In several countries, clinicians often use benzodiazepines (either alone or in combination with antipsychotics) for this outcome. OBJECTIVES: To examine whether benzodiazepines, alone or in combination with other pharmacological agents, is an effective treatment for psychosis-induced aggression or agitation when compared with placebo, other pharmacological agents (alone or in combination) or non-pharmacological approaches. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's register (January 2012, 20 August 2015 and 3 August 2016), inspected reference lists of included and excluded studies, and contacted authors of relevant studies. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing benzodiazepines alone or in combination with any antipsychotics, versus antipsychotics alone or in combination with any other antipsychotics, benzodiazepines or antihistamines, for people who were aggressive or agitated due to psychosis. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality assessed them and extracted data. For binary outcomes, we calculated standard estimates of risk ratio (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean difference (MD) between groups. If there was heterogeneity, this was explored using a random-effects model. We assessed risk of bias and created a 'Summary of findings' table using GRADE. MAIN RESULTS: Twenty trials including 695 participants are now included in the review. The trials compared benzodiazepines or benzodiazepines plus an antipsychotic with placebo, antipsychotics, antihistamines, or a combination of these. The quality of evidence for the main outcomes was low or very low due to very small sample size of included studies and serious risk of bias (randomisation, allocation concealment and blinding were not well conducted in the included trials, 30% of trials (six out of 20) were supported by pharmaceutical institutes). There was no clear effect for most outcomes.Benzodiazepines versus placeboOne trial compared benzodiazepines with placebo. There was no difference in the number of participants sedated at 24 hours (very low quality evidence). However, for the outcome of global state, clearly more people receiving placebo showed no improvement in the medium term (one to 48 hours) (n = 102, 1 RCT, RR 0.62, 95% CI 0.40 to 0.97, very low quality evidence). Benzodiazepines versus antipsychoticsWhen compared with haloperidol, there was no observed effect for benzodiazepines for sedation by 16 hours (n = 434, 8 RCTs, RR 1.13, 95% CI 0.83 to 1.54, low quality evidence). There was no difference in the number of participants who had not improved in the medium term (n = 188, 5 RCTs, RR 0.89, 95% CI 0.71 to 1.11, low quality evidence). However, one small study found fewer participants improved when receiving benzodiazepines compared with olanzapine (n = 150, 1 RCT, RR 1.84, 95% CI 1.06 to 3.18, very low quality evidence). People receiving benzodiazepines were less likely to experience extrapyramidal effects in the medium term compared to people receiving haloperidol (n = 233, 6 RCTs, RR 0.13, 95% CI 0.04 to 0.41, low quality evidence).Benzodiazepines versus combined antipsychotics/antihistaminesWhen benzodiazepine was compared with combined antipsychotics/antihistamines (haloperidol plus promethazine), there was a higher risk of no improvement in people receiving benzodiazepines in the medium term (n = 200, 1 RCT, RR 2.17, 95% CI 1.16 to 4.05, low quality evidence). However, for sedation, the results were controversial between two groups: lorazepam may lead to lower risk of sedation than combined antipsychotics/antihistamines (n = 200, 1 RCT, RR 0.91, 95% CI 0.84 to 0.98, low quality evidence); while, midazolam may lead to higher risk of sedation than combined antipsychotics/antihistamines (n = 200, 1 RCT, RR 1.13, 95% CI 1.04 to 1.23, low quality evidence).Other combinationsData comparing benzodiazepines plus antipsychotics versus benzodiazepines alone did not yield any results with clear differences; all were very low quality evidence. When comparing combined benzodiazepines/antipsychotics (all studies compared haloperidol) with the same antipsychotics alone (haloperidol), there was no difference between groups in improvement in the medium term (n = 185, 4 RCTs, RR 1.17, 95% CI 0.93 to 1.46, low quality evidence), but sedation was more likely in people who received the combination therapy (n = 172, 3 RCTs, RR 1.75, 95% CI 1.14 to 2.67,very low quality evidence). Only one study compared combined benzodiazepine/antipsychotics with antipsychotics; however, this study did not report our primary outcomes. One small study compared combined benzodiazepines/antipsychotics with combined antihistamines/antipsychotics. Results showed a higher risk of no clinical improvement (n = 60, 1 RCT, RR 25.00, 95% CI 1.55 to 403.99, very low quality evidence) and sedation status (n = 60, 1 RCT, RR 12.00, 95% CI 1.66 to 86.59, very low quality evidence) in the combined benzodiazepines/antipsychotics group. AUTHORS' CONCLUSIONS: The evidence from RCTs for the use of benzodiazepines alone is not good. There were relatively few good data. Most trials were too small to highlight differences in either positive or negative effects. Adding a benzodiazepine to other drugs does not seem to confer clear advantage and has potential for adding unnecessary adverse effects. Sole use of older antipsychotics unaccompanied by anticholinergic drugs seems difficult to justify. Much more high-quality research is still needed in this area.

Inclusion of the value of herd immunity in economic evaluations of vaccines. A systematic review of methods used.

OBJECTIVE: The objectives of this review were to identify vaccine economic evaluations that include herd immunity and describe the methodological approaches used. METHODS: We used Kim and Goldie's search strategy from a systematic review (1976-2007) of modelling approaches used in vaccine economic evaluations and additionally searched PubMed/MEDLINE and Embase for 2007-2015. Studies were classified according to modelling approach used. Methods for estimating herd immunity effects were described, in particular for the static models. RESULTS: We identified 625 economic evaluations of vaccines against human-transmissible diseases from 1976 to 2015. Of these, 172 (28%) included herd immunity. While 4% of studies included herd immunity in 2001, 53% of those published in 2015 did this. Pneumococcal, human papilloma and rotavirus vaccines represented the majority of studies (63%) considering herd immunity. Ninety-five of the 172 studies utilised a static model, 59 applied a dynamic model, eight a hybrid model and ten did not clearly state which method was used. Relatively crude methods and assumptions were used in the majority of the static model studies. CONCLUSION: The proportion of economic evaluations using a dynamic model has increased in recent years. However, 55% of the included studies used a static model for estimating herd immunity. Values from a static model can only be considered reliable if high quality surveillance data are incorporated into the analysis. Without this, the results are questionable and they should only be included in sensitivity analysis.

The Yusuf-Peto method was not a robust method for meta-analyses of rare events data from antidepressant trials.

OBJECTIVES: The aim of the study was to identify the validity of effect estimates for serious rare adverse events in clinical study reports of antidepressants trials, across different meta-analysis methods. STUDY DESIGN AND SETTING: Four serious rare adverse events (all-cause mortality, suicidality, aggressive behavior, and akathisia) were meta-analyzed using different methods. The Yusuf-Peto odds ratio ignores studies with no events and was compared with the alternative approaches of generalized linear mixed models (GLMMs), conditional logistic regression, a Bayesian approach using Markov Chain Monte Carlo (MCMC), and a beta-binomial regression model. RESULTS: The estimates for the four outcomes did not change substantially across the different methods; the Yusuf-Peto method underestimated the treatment harm and overestimated its precision, especially when the estimated odds ratio deviated greatly from 1. For example, the odds ratio for suicidality for children and adolescents was 2.39 (95% confidence interval = 1.32-4.33), using the Yusuf-Peto method but increased to 2.64 (1.33-5.26) using conditional logistic regression, to 2.69 (1.19-6.09) using beta-binomial, to 2.73 (1.37-5.42) using the GLMM, and finally to 2.87 (1.42-5.98) using the MCMC approach. CONCLUSION: The method used for meta-analysis of rare events data influences the estimates obtained, and the exclusion of double-zero event studies can give misleading results. To ensure reduction of bias and erroneous inferences, sensitivity analyses should be performed using different methods instead of the Yusuf-Peto approach, in particular the beta-binomial method, which was shown to be superior through a simulation study.